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OVERVIEW OF CANCER
PATHOPHYSIOLOGY
Cynthia Smith, RN, BA, MSN, AOCN
Oncology Clinical Nurse Specialist
Harrison Medical Center
A Few Definitions to Get Us Started… Physiology - A science that deals with the ways that living things function
- The ways that living things or any of their parts function
- A branch of biology that deals with functions & activities of life or of living matter (as organs, tissues, or cells) & of physical / chemical phenomena
- Organic processes & phenomena of an organism or any of its parts or of a particular bodily process
Pathophysiology - The physiology of abnormal states; specifically: the functional changes
that accompany a particular syndrome or disease
Cancer - Northern zodiacal constellation between Gemini & Leo: 4th zodiak sign
in astrology. From Latin, crab, cancer
- Malignant tumor of potentially unlimited growth: expands locally by invasion and systemically by metastasis; abnormal body state marked by such tumors
- Evil / malignant thing spreads destructively, e.g. cancer of hidden
resentment
Definition: Cancer
Source: J. Eggert, Ed. (2010). In Cancer Basics Online Education Series, “Biology of
Cancer – Chapter 1”, Oncology Nursing Society: Pittsburgh, PA . Accessed 8-24-15.
Defining Targeted Molecular Therapy
• Targeted molecular therapy uses drugs or substances to interfere
with specific molecules so can block tumor growth and proliferation
• These drugs or substances work by disrupting or blocking cell
communication signals 1 of 2 locations:
- From the outside of the cell to the inside of the cell
- Inside the cell so that signals do not reach the nucleus to
instruct the cell to divide, or make proteins
• Targeted therapies can be categorized according to effects on
cancer hallmarks. Are divided into 2 broad categories: small
molecule (suffix “ib”or“tib”) & monoclonal antibodies (suffix “mab”)
Wilkes, G. “Targeted Therapies”. (2016). In InPractice: Oncology Nursing Cancer Treatments
Targeted Therapies. SanFilippo, Camp-Sorell, D., & Hawkins, R. eds. Oncology Nursing Society:
Pittsburgh, PA. Accessed 8-30-16 at: https://www.inpractice.com/Textbooks/Oncology-
Nursing/Cancer-Treatments/Targeted-Therapies/Summary.aspx
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Setting the Stage: Why is Cancer
Pathophysiology / Biology Important?
Classification of Cancer Biomarkers by Function
Personalized Medicine: Genetic Biomarkers
- Advanced tests analyze tumor samples, other tissue for
abnormal gene feature (allow cancer to develop or spread)
- May look at single gene OR entire chromosome. With
tests, researchers look for genetic mutations / alterations
in some tumors to help guide treatment decisions, e.g.
look for genetic profile or fingerprint.
- Limited to breast and colorectal cancer. Tests improve care
as the right person is matched to the right treatment plan
- OncotypeDX – calculates recurrence score. Measures
activity 16 cancer genes, 5 control genes
Personalized Medicine: Protein Biomarker
- Include substances that are either produced by cancer
cells themselves or by other cells in response to
cancer.
- Most protein biomarkers related to cancer are used to
monitor response and/or detect recurrence or
progression during follow-up after treatment.
- Some biomarkers used to predict outcome or prognosis
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Protein Biomarkers for Cancer Types Protein Biomarkers for Cancer Types
Objectives. By the end of this
presentation, participants will be able to:
• Describe 3 parts of a cell’s anatomy & list 3 normal functions
• Review angiogenesis in normal cell functioning
• Explain how cell signaling affects normal cell function
• Describe how genetic mutations lead to malignant transformation
• Explore theories of carcinogenesis
• State how cell signaling influences the cell cycle in a cancer cell.
• Identify steps in malignant angiogenesis and metastases
• Describe the common signal transduction pathways identified in
the development of new therapeutic cancer agents
• Identify several therapeutic agents approved to target the signal
transduction pathways commonly associated with malignancy
Normal Cell Anatomy and Function
Cell Anatomy:
• Cell Membrane
• Receptors: Extracytoplasmic, transmembrane, intracytoplasmic
• Organelles: Mitochrondria, smooth / rough endoplasmic
reticulum, lysosomes, proteosomes
• Nucleus: RNA (messenger, translation, & transcription), DNA,
chromosomes, genes, nucleolus, nucleotides (base pairs)
Cell Function:
• Signaling pathways – activate or inhibit genetic signals
• Protein production unique to cell type (surfactant, insulin)
• Produce energy (ATP): aerobic (Kreb’s cycle) Anaerobic
glycolosis (lactic acid)
• Cell replication / Programmed cell death (apoptosis)
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Cell Schematic DNA Packaging
Source: J. Eggert, Ed. (2010). In Cancer Basics Online Education Series, “Biology of
Cancer– Chapter 1”, Oncology Nursing Society: Pittsburgh, PA . Accessed 8-24-15.
Structure / Function of DNA and Chromosomes DNA is Copied During Cell Division
• The DNA “parent” strands pull apart
• Complementary bases are added
• (A-T, C-G)
• The result is two complete DNA molecules that are an exact copy of the original molecule
• Each cell gets a complete copy
Adapted: “Mapping Our Genes: The Genome Projects: How Big, How Fast?” by U.S. Congress,
Office of Technology Assessment, OTA- BA- 373 (Washington, DC: U.S. Gov. Print Office, 1988).
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Cell Life Cycle Regulation of the Cell Cycle
Donovan, J. et.al. (2005). Cell Proliferation and Tumor Growth. In Tannock, I.,
et.al., ed(s), The Basic Science of Oncology.
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Differences between malignant & normal cells Genetic Mutations
Mutated cell may:
• Die from damage or
by initiating
programmed cellular
suicide (apoptosis)
• Recognize damage
and repair itself
• Survive and pass on
damage
Volker, D. (2005). Biology of Cancer and Carcinogenesis. In Itano, K. & Taoka, J. (Eds), Core
Curriculum for Oncology Nursing (4th ed, pp. 443-478), Pittsburgh: Oncology Nursing Society.
Genetic mutations: Acquired or hereditary?
Genes can become mutated, or abnormal, if the DNA sequence is changed.
Change in gene’s DNA sequence usually causes the protein it helped to build
to either not function normally or not function at all.
Result? Growth, division or survival of cells may be abnormal. Changes in DNA
sequences occur often, mostly during cell division, but DNA can fix these
errors (p53 tumor suppressor gene / DNA repair gene). Sometimes, repair
method fails & the genetic mutation passes on to future copies of changed cell.
The most common types of mutations in cancer involve four abnormalities:
1) AMPLIFICATION: Increase in # copies of a specific DNA fragment DNA
2) DELETION: Loss of genetic material, ranging from small (a single missing
DNA base pair) to large (a piece of a chromosome)
3) INACTIVATION: Loss of the biologic function of the gene
4) TRANSLOCATION: A broken chromosome reattaches to a different one BCR-ABL inhibitors used to treat CML: Dasatinib, Imatinib, Nilotinib, Ponatinib
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Genetic Mutations:
Somatic (Acquired) vs. Germline (Inherited)
Source: National Cancer Institute.
Retrieved 8-24-15 at: www.nci.gov
Somatic Genetic Mutations
Genes important in Carcinogenesis
1. Apoptosis Gene (programmed cell death)’ this gene is shut down / inactivated in cancer
2. DNA Repair Gene (repair abnormal copy / signal cell
if can’t )
3. Proto-oncogene (signals cell to begin replicating,
enter cell cycle). Mutations to gene transform it,
making gene oncogenic. Continuous signals to divide
4. Tumor suppressor gene (instructs cell – stop
dividing). Mutations here are like losing car brakes;
cell never receives signal to stop dividing
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Angiogenesis
• Normally only present if require wound healing or during pregnancy when gene is activated
• Recruit elements to build new vasculature, capillaries:
- Endothelial cells - Fibroblasts - Epidermal cells
• Respond to messages / signaling of vascular endothelial growth factor (VEG-F), fibroblast growth factor (FBG-F), & epidermal growth factor
• Malignant angiogenesis: tumor makes VEG-F, FBG-F in conditions of hypoxia, need for nutrients, waste disposal, promote metastases
• Therapeutic Anti-angiogenic agents: Thaladomide (Thaladomid®, Cetuximab (Erbitux®) – Blocks VEG-R receptor on endothelial cell)
• Bevacizamab (Avastin®) – Binds with VEG ligand prior to VEGF-R
Angiogenesis
Steps in Angiogenesis So What Causes Cancer?
Source: J. Eggert, Ed. (2010). In Cancer Basics Online Education Series, “Biology of
Cancer– Chapter 1”, Oncology Nursing Society: Pittsburgh, PA . Accessed 8-24-15.
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Carcinogenesis
Source: J. Eggert, Ed. (2010). In Cancer Basics Online Education Series, “Biology of
Cancer– Chapter 1”, Oncology Nursing Society: Pittsburgh, PA . Accessed 8-24-15.
Molecular Basis of Cancer
Cotran, RS, Kumar, V, Robbins, SL: Molecular Basis of Cancer. (1999) In Robbins Pathologic Basis
of disease, (5th ed.), WB Saunders: Philadelphia, PA.
New Research: Stress & Inflammation
Combine to Fuel Cancer Growth Definitions
• Stress: Experience of significant or negative life event or an event without effective coping. Psychological / physiologic response to body perceives as a threat.
• Inflammation: Cellular manifestation stress. “Acute”, i.e. innate immunity activates immune system to ward off infection or “Chronic”, i.e. lingering inflammation can predispose individuals to illness such as cancer.
• Stress & inflammation probably mediate cancer development & progressions. 25% of cancers are associated with chronic inflammation of broad origin.
Source: http://connect.ons.org/columns/five-minute-in-service/stress-and-inflammation
New Research: Stress & Inflammation
Combine to Fuel Cancer Growth • Many cancer-related deaths caused by treatment resistant-
metastases. Stress & inflammation drive metastatic process.
• Body produces pro-inflammatory markers such as cytokines in response to stress. Cytokines regulate immune responses and inflammation. Two pro-inflammatory cytokines are interleukins & tumor necrosis factor; these turn on various transcription factors.
• Inflammation changes tissue homeostasis; leads to chronic response promotes tumor growth, angiogenesis, invasion and metastasis by activating surrounding stromal cells & recruiting inflammatory cells (e.g. mast & NK, neutrophils & leukocytes).
• Inflammatory cells create reactive O2 & Nitrogen species, turn on oncogenes, and silence tumor suppressor genes
Source: http://connect.ons.org/columns/five-minute-in-service/stress-and-inflammation
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Psycho-Oncology Interventions for Managing
Stress and Inflammation in Cancer
• Mind-body techniques * Yoga
• Mindfulness * Cognitive / Behavioral therapy
• Meditation * Energy-Based Techniques
• Reiki * Acupuncture
• Acupressure * Meridian tapping
• Natural Products * Vitamins and minerals
• Botanicals * Fish Oils
• Probiotics * Exercise
• Walking * Swimming / Hiking
• Bicycling * Zumba / Dance Fitness
Source: Payne, J.K. (2014). State of the Science: Stress, Inflammation, and
Cancer. Oncology Nursing Forum, 41(5), 533-540.
Theories of Cancer Development
Knudson 2 Hit Theory of Cancer Development
Source: J. Eggert, Ed. (2010). In Cancer Basics Online Education Series, “Biology of
Cancer– Chapter 1”, Oncology Nursing Society: Pittsburgh, PA . Accessed 8-24-15.
Cancer Stem Cell Theory
Source: J. Eggert, Ed. (2010). In Cancer Basics Online Education Series, “Biology of
Cancer– Chapter 1”, Oncology Nursing Society: Pittsburgh, PA . Accessed 8-24-15.
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Many Cancer Types Caused by “Bad Luck”
of Random Mutations (Source: Science 1-2-15)
• Cancer often strikes individuals without any type of known risk factors; new research says many cancer types due to “bad luck”
• With statistical model measuring proportion of cancer incidence across 31 tissue types, Johns Hopkins Univ. School of Medicine researchers found that 22 cancers, (2/3’s of the total reviewed), could be largely explained by "bad luck" or random mutations during DNA replication in normal, non-cancerous stem cells.
• The remaining 9 cancer types were more attributable to environmental, lifestyle, and hereditary factors.
• Focus on stem cell division–the more divisions taking place e.g. stem cell turn-over, the more prone tissue is to develop cancer
The Metastatic Process
The Metastatic Process The Metastatic Process
Overall most common sites of metastases
• Bone
• Brain
• Liver
• Lungs
• Lymph nodes
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Pathologic Diagnosis of Cancer
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Pathologic Diagnosis of Cancer
Grading and Differentiation
• GX Grade can not be assessed
• G1 Well-differentiated (Low grade)
• G2 Moderately-differentiated
• G3 Poorly-differentiated
• G4 Undifferentiated (High grade)
Grade: Degree to which tumor cells resemble
parent tissue
Tumor Grade
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TMN Staging • T = TUMOR Local involvement, invasion
e.g. extent of primary tumor
• N = NODES Lymph node involvement, e.g.
presence / absence of regional
lymph node metastases
• M = METASTASIS Distant location(s), e.g.
presence or absence of distant
metastases
TMN Staging for Lung Cancer TMN Staging for Lung Cancer
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TMN Staging for Lung Cancer Advances in Cancer Therapy • Oncogenes, when mutated or expressed aberrantly, disrupt normal
signaling pathways to allow cells to divide continuously and invade
adjacent tissues & metastasize to distant body organs
• Thriving cancer cells must continually divide, evade tumor
suppressors & immune system, an environment conducive to
growth, an adequate blood supply, avoid programmed cell death, &
use cellular energy (glycolysis)
• Newer trial designs such as “umbrella” or “basket” trials are being
used to speed evaluation of targeted therapies,
• Molecular targeted therapy blocks signals that stimulate cancer
cells to grow and proliferate, to invade, and to metastasize
Wilkes, G. “Targeted Therapies”. (2016). In InPractice: Oncology Nursing Cancer Treatments
Targeted Therapies. SanFilippo, Camp-Sorell, D., & Hawkins, R. eds. Oncology Nursing Society:
Pittsburgh, PA. Accessed 8-30-16 at: https://www.inpractice.com/Textbooks/Oncology-
Nursing/Cancer-Treatments/Targeted-Therapies/Summary.aspx
National Cancer Institute “MATCH” trial • NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) is a
clinical trial to analyze tumors to see whether they contain genetic
abnormalities for which a targeted drug exists (i.e., “actionable
mutations”). Treatment assigned based on abnormality.
• Trial seeks to determine whether treating cancers according to their
molecular abnormalities will show evidence of effectiveness.
• Trial opened for enrollment in Aug. 2015 with 10 arms. Each arm to
enroll adults >18 y.o. with advanced solid tumors & lymphomas that
no longer respond (or never responded) to standard therapy & are
growing. Accrual goal each arm-1000. Trial endpoint ORR (CR, PR)
• Plan to obtain tumor biopsy specimens (3000) for DNA sequencing
to identify those with genetic abnormalities that may respond to the
targeted drugs on trial. Testing 20 FDA-approved targeted agents.
Types of targeted molecular therapy: Angiogenesis inhibitors BCR-ABL inhibitors
BRAF and MEK inhibitors BTK inhibitors
EGFR inhibitors HDAC inhibitors
Multikinase inhibitors PARP inhibitors
PI3K inhibitors Proteasome inhibitors
Cyclin-dependent kinase inhibitors Hedgehog pathway inhibitors
Mammalian target of rapamycin (mTOR) inhibitors
Wilkes, G. “Targeted Therapies”. (2016). In InPractice: Oncology Nursing Cancer Treatments -
Targeted Therapies. SanFilippo, Camp-Sorell, D., & Hawkins, R. eds. Oncology Nursing Society:
Pittsburgh, PA. Accessed 8-30-16 at: https://www.inpractice.com/Textbooks/Oncology-
Nursing/Cancer-Treatments/Targeted-Therapies/Summary.aspx
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Can we use the photo on page 35 of the new text
under this section heading
It is a photo from IMER
Signal Inhibition in the cytoplasm: Small molecule inhibitors,
mTOR Inhibitors, PARP inhibitors & Proteasome Inhibitors Extracellular Receptor Inhibition via
Monoclonal Antibody Mechanism of Action
Targeted Therapy • Targeted therapy is selective to specific proteins, antigens,
pathways, or processes, and associated with fever and less-
severe side effects
• Side effects from targeted therapy are specific to the drug, class
of agents, or the cellular target
• Targeted therapy is dosed at the biologically active dose
• Small molecule–targeted therapies are able to pass through cell
membrane to interfere with normal cell functions and processes
• Small molecule therapies are given orally but monoclonal
antibodies (large molecules) are administered intravenously
Wilkes, G. “Targeted Therapies”. (2016). In InPractice: Oncology Nursing Cancer Treatments Targeted
Therapies. SanFilippo, Camp-Sorell, D., & Hawkins, R. eds. Oncology Nursing Society: Pittsburgh, PA.
Accessed 8-30-16 at: https://www.inpractice.com/Textbooks/Oncology-Nursing/Cancer-
Treatments/Targeted-Therapies/Summary.aspx
Communication • Identifying the Target
• Cells are instructed by messages from outside the cell, which pass
through cell surface receptors (cell signaling)
• These messages, and other messages from inside the cell are
delivered to the cell nucleus by a process called signal transduction
• Receptor tyrosine kinases and non–receptor tyrosine kinases are
proteins that carry the message
• Signal Transduction
• A receptor tyrosine kinase (RTK) is made of extracellular (outside
cell), transmembrane (across membrane) & cytoplasmic parts
• When a ligand attaches to a receptor, dimerization occurs; this
activates phosphorylation & sends message through the cell
membrane to activate the cytoplasmic tyrosine kinase
• Cell’s energy moves message “downstream” towards cell nucleus
• Communication from outside cell to nucleus is signal transduction.
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Cellular Communication
• Nonreceptor Tyrosine Kinases
• nRTKs regulate differentiation, growth, division, adhesion, and survival
• Mutation of nRTK genes can alter the transmission of messages to the cell
nucleus allowing uncontrolled and continuous growth and proliferation
• Therapeutic targets include mTOR, and within the MAPK pathway, RAS,
RAF, MEK, ERK and c-Kit
• Cancer and Signal Transduction
• In cancer cells, components of signal transduction pathways are often
mutated (eg, RAS, BRAF), enabling cell nucleus to receive continuous
signals to proliferate, grow & not respond to programmed cell death
• Continual genetic mutation within tumor cells can lead to the development
of alternate pathways and subsequent drug resistance
Wilkes, G. “Targeted Therapies”. (2016). In InPractice: Oncology Nursing Cancer Treatments Targeted
Therapies. SanFilippo, Camp-Sorell, D., & Hawkins, R. eds. Oncology Nursing Society: Pittsburgh, PA.
Accessed 8-30-16 at: https://www.inpractice.com/Textbooks/Oncology-Nursing/Cancer-
Treatments/Targeted-Therapies/Summary.aspx
Figure 1: Where’s the target?
Wilkes, G. “Targeted Therapies”. (2016). In InPractice: Oncology Nursing Cancer Treatments Targeted
Therapies. SanFilippo, Camp-Sorell, D., & Hawkins, R. eds. Oncology Nursing Society: Pittsburgh, PA.
Accessed 8-30-16 at: https://www.inpractice.com/Textbooks/Oncology-Nursing/Cancer-
Treatments/Targeted-Therapies/Summary.aspx
Biology Application: Downstream KRAS Oncogene
Pathway target in Lung Adenocarcinoma
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Biology Application: Checkpoint inhibitors
for Advanced Melanoma
New drugs act as PD-1 receptors; are monoclonal antibodies
1) First drug – ipilimumab (Yervoy™) approved in 2011
2) Second drug - pembrolizumab (Ketruda™) approved in 2014
3) Third drug - nivolumab (Opdivo™) approved in 2014
• Immune system uses feedback loop to regulate self; at check-points, receives signals telling it to slow down or turn off. Goal: to prevent over-activation or attack of body’s own cells. Tumors express such signals with the end result the body’s natural cancer defenses are limited.
• Checkpoint inhibitor drugs block the tumor’s signals: thus, immune system is up-regulated & body’s natural defense against cancer cells is enhanced.
Biology Application: Co-treating Hairy Cell Leukemia
and Melanoma with BRAF Inhibitor, Dabrafenib and
MEK Inhibitor, Trametinib • The activating BRAF mutation has been identified in many cancers,
including: colon & lung adenocarcinomas, papillary thyroid cancer,
malignant melanoma & hairy cell leukemia.
• Malignant melanoma & HCL are of particular interest because of both
the high proportion of cases harboring the mutation and the dramatic
responses to BRAF inhibitor therapy reported in the literature.
• Patients with Hairy Cell Leukemia & malignant melanoma present
with the BRAF p.V600E mutation, but may be successfully treated for
both cancers with the BRAF inhibitor dabrafenib (Tafinlar).
• Source: http://www.jnccn.org/content/13/1/9
Are you beginning to appreciate why
understanding cancer biology is critical?
• Cancer Moonshot Initiative: Vice-President Joe Biden – Research funding for cure
• Personalized medicine / Molecular profiling
• Genetic mutations and actionable targets
• Biosimilars
• New side effect profiles and management
• Patient / family / provider education needed
• Cancer as a chronic disease: 20 million survivors by 2020 (NCCS)
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Questions?